Alterations in gut microbiota impact the pathophysiology of several diseases, including cancer. Radiotherapy (RT), an established curative and palliative cancer treatment, exerts potent immune modulatory effects, inducing tumor-associated antigen (TAA) cross-priming with antitumor CD8+ T cell elicitation and abscopal effects. We tested whether the gut microbiota modulates antitumor immune response following RT distal to the gut. Vancomycin, an antibiotic that acts mainly on gram-positive bacteria and is restricted to the gut, potentiated the RT-induced antitumor immune response and tumor growth inhibition. This synergy was dependent on TAA cross presentation to cytolytic CD8+ T cells and on IFN-γ. Notably, butyrate, a metabolite produced by the vancomycin-depleted gut bacteria, abrogated the vancomycin effect. In conclusion, depletion of vancomycin-sensitive bacteria enhances the antitumor activity of RT, which has important clinical ramifications.

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Gut microbiota modulate dendritic cell antigen presentation and radiotherapy-induced antitumor immune response

Recent evidence indicates that ionizing radiation can enhance immune responses to tumors. Advances in radiation delivery techniques allow hypofractionated delivery of conformal radiotherapy. Hypofractionation or other modifications of standard fractionation may improve radiation's ability to promote immune responses to tumors. Other novel delivery options may also affect immune responses, including T-cell activation and tumor-antigen presentation changes. However, there is limited understanding of the immunological impact of hypofractionated and unique multifractionated radiotherapy regimens, as these observations are relatively recent. Hence, these differences in radiotherapy fractionation result in distinct immune-modulatory effects. Radiation oncologists and immunologists convened a virtual consensus discussion to identify current deficiencies, challenges, pitfalls and critical gaps when combining radiotherapy with immunotherapy and making recommendations to the field and advise National Cancer Institute on new directions and initiatives that will help further development of these two fields.This commentary aims to raise the awareness of this complexity so that the need to study radiation dose, fractionation, type and volume is understood and valued by the immuno-oncology research community. Divergence of approaches and findings between preclinical studies and clinical trials highlights the need for evaluating the design of future clinical studies with particular emphasis on radiation dose and fractionation, immune biomarkers and selecting appropriate end points for combination radiation/immune modulator trials, recognizing that direct effect on the tumor and potential abscopal effect may well be different. Similarly, preclinical studies should be designed as much as possible to model the intended clinical setting. This article describes a conceptual framework for testing different radiation therapy regimens as separate models of how radiation itself functions as an immunomodulatory 'drug' to provide alternatives to the widely adopted 'one-size-fits-all' strategy of frequently used 8 Gy×3 regimens immunomodulation.

https://jitc.bmj.com/content/jitc/9/4/e002038.full.pdf

Radiation dose and fraction in immunotherapy: one-size regimen does not fit all settings, so how does one choose?

Except for its use in palliative care, radiotherapy has been largely abandoned in the management of ovarian cancer because of the recognised efficacy and lower toxicity of systemic chemotherapy compared with radiotherapy. New data have emerged that show synergy of radiotherapy with immunotherapy to control or eradicate cancer. Different doses of hypofractionated radiotherapy have been shown to induce immunogenic cell death and in-situ vaccination in several tumour models. However, doses less than 2 Gy can also reprogramme the tumour microenvironment. This Series paper discusses the past and present use of radiotherapy for ovarian cancer, and the mechanisms by which radiotherapy can mobilise anticancer immunity. We provide emerging preclinical and clinical data for combining immunotherapy with radiotherapy for ovarian cancer treatment and offer a clinical development roadmap to guide the next generation of clinical trials for this combination strategy for this disease.

Rational combinations of immunotherapy with radiotherapy in ovarian cancer

Mounting evidence suggests that radiation stimulates the immune system and this contributes to the abscopal effect, which is defined as "response at a distance from the irradiated volume." Though identified more than 50 years ago, the abscopal effect is revisited today. One rationale is that the abscopal effect is often observed with efficient immunotherapy. Here, we give an overview of the clinical data on the abscopal effect, generated by a combination of immunotherapy and radiotherapy (RT). Only papers that included RT in combination with immunotherapy were evaluated according to four main categories including RT parameters, sequencing of therapies, the definition of the abscopal effect, and patient selection. Twenty-four cases in 15 reports were reviewed. The results varied. Patient ages ranged from 24 to 74. RT dose (median total dose 18-58 Gy) varied. Biologically effective dose (BED) 10 was calculated to be a median 49.65 Gy (28-151 Gy). The time to a documented abscopal response ranged from less than a month to 12 months. The large variation concerning fractionation and sequencing of therapies indicates that these conflicting points need to be resolved, to generate for the abscopal effect to be clinically significant.

Abscopal Effect of Radiotherapy in the Immunotherapy Era: Systematic Review of Reported Cases

Pneumonitis is a potential consequence of both lung-directed radiation and immune checkpoint blockade (ICB), particularly treatment with PD-1/PD-L1 inhibitors. Significant morbidity and mortality can result, and severe pneumonitis attributed to ICB precludes continued therapy. Thus, discriminating between radiation- and ICB- related pneumonitis is of importance for the increasing number of patients receiving both treatments. Furthermore, data are limited regarding the interplay between radiation- and ICB-induced lung injury, and which biomarkers might be associated with toxicity. We report longitudinal clinical and radiologic data, and circulating biomarkers in a melanoma patient treated with axillary radiation followed by ICB who developed consolidation and ground glass opacities (GGO) within the radiation field suggestive of radiation-pneumonitis followed by consolidation outside of the radiation field suggestive of ICB-related pneumonitis. Of note, symptomatic radiation-pneumonitis developed despite a low radiation dose to the lung (V20 < 8%), and ICB-related pneumonitis was limited to the ipsilateral lung, suggesting additive effect of radiation and ICB in the development of lung injury. Circulating biomarker analyses demonstrated increases in CXCR2, IL1ra and IL2ra that coincided with the development of symptomatic pneumonitis. These data highlight the imaging findings associated with radiation and ICB-related lung toxicity, and anecdotally describe a clinical course with circulating biomarker correlates. This information can help guide clinical evaluation and future research investigations into the toxicity of combined radiation immunotherapy approaches.

https://jitc.bmj.com/content/jitc/7/1/112.full.pdf

Pneumonitis resulting from radiation and immune checkpoint blockade illustrates characteristic clinical, radiologic and circulating biomarker features.

We conducted a phase I trial evaluating pembrolizumab+hypofractionated radiotherapy (HFRT) for patients with metastatic cancers. There were two strata (12 patients each): (i) NSCLC/melanoma progressing on prior anti-PD-1 therapy, (ii) other cancer types; anti-PD-1-naive. Patients received 6 cycles of pembrolizumab, starting 1 week before HFRT. Patients had ≥2 lesions; only one was irradiated (8 Gy × 3 for first half; 17 Gy × 1 for second half in each stratum) and the other(s) followed for response. Of the 24 patients, 20 (83%) had treatment-related adverse events (AEs) (all grade 1 or 2). There were eight grade 3 AEs, none treatment related. There were no dose-limiting toxicities or grade 4/5 AEs. Stratum 1: two patients (of 12) with progression on prior PD-1 blockade experienced prolonged responses (9.2 and 28.1 months). Stratum 2: one patient experienced a complete response and two had prolonged stable disease (7.4 and 7.0 months). Immune profiling demonstrated that anti-PD-1 therapy and radiation induced a consistent increase in the proliferation marker Ki67 in PD-1-expressing CD8 T cells. HFRT was well tolerated with pembrolizumab, and in some patients with metastatic NSCLC or melanoma, it reinvigorated a systemic response despite previous progression on anti-PD-1 therapy. Clinical Trial Registration: NCT02303990 (
 www.clinicaltrials.gov
 ).

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Lilie L. Lin

Papers

A phase I trial of pembrolizumab with hypofractionated radiotherapy in patients with metastatic solid tumours.